Chapter 8

Surgical Treatment Strategies andPrognosis of Hepatocellular Carcinoma

Alessandro Uzzau, Maria Laura Pertoldeo,Vittorio Cherchi, Serena Bertozzi,Claudio Avellini and Giorgio Soardo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55890

1. Introduction

Hepatocellular carcinoma (HCC is the fifth most common cause of mortality worldwide andthe third cancer related cause and is responsible for about 1 million deaths yearly [1]. The age-adjusted worldwide incidence is 5.5-14.9 per 100.000 population. In some areas of the world,such as sub-Saharan Africa and Southeast Asia, HCC represents the first cause of cancer deathwith an incidence of 52 per 100.000. Furthermore, in Europe and USA, HCC incidence hasprogressively raised in the past decade representing a burden problem.

HCC is one of the few cancers for which a number of risk factors are known in great detail [2,3]. HCC is almost always (80%) associated with cirrhosis, at least in developed countries, andchronic hepatitis C and B infection, alcoholic cirrhosis and haemocromatosis are some of theestablished risk factors [4]. The metabolic syndrome related to hypertension, central obesity,diabetes and obesity has been identified as a new risk factor. As a result, screening programshave developed, with the use of ultrasound and α-fetoprotein (AFP), with a hope to increasethe chances of diagnosing small HCC and unltimately increase the rate of curability.

Definitive diagnosis relies on the demonstration of a typical vascular pattern per liver imagingtechniques (triple-phase CT-scan or MRI) of tumors larger than 2 cm with arterial hypervascu‐larity and venous wash- out. Nodules, smaller than 2 cm, should be rechecked every six monthsor, if highly suspect, subjected to needle biopsy. It’s likely that the study of tumor-specific tissuemarkers with prognostic value could introduce a systematic use of needle biopsy.

Over the past 20 years, surgical treatment of hepatocellular carcinoma has seen an immenseboost and improvement, with good survival outcomes and reduced morbidity and mortality.

© 2013 Uzzau et al.; licensee InTech. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.

Liver resection (LR) and orthotopic liver transplantation (OLT) and ablative therapies are nowconsidered the only potentially curative treatments for this cancer. LR has achieved improve‐ment in survival within the past decade as a result of advances in diagnosis, surgical man‐agement of HCC and perioperative care. However, the long-term prognosis remains poor, andthe 5-year overall survival rate ranges between 33% and 44%, with a 5-year cumulativerecurrence rate of 80% to 100%.

OLT could be viewed as the optimal treatment for HCC that is accompanied by advancedcirrhosis because of the widest possible resection margins for tumour and for a definitive cureof cirrhosis and its related complications. OLT for HCC performed within well-definedoncologic criteria (Milan criteria “reference”) has shown long-term results comparable withthose of transplantation for non-HCC patients. However, the critical shortage of availabledonated organs, together with the increasing number of patients awaiting transplantation,makes this therapeutic option available to only a small percentage of patients. Owing to thelimited organ supply, many liver transplant centers usually make a selection to resect patientswith compensated liver cirrhosis, defined as Child–Pugh A chronic liver disease and resectabletumor and to reserve transplantation for those with impaired liver function (Child-Pugh classB-C) and small oligonodular HCC considered within the currently accepted criteria fortransplantation.

Radiofrequency and microwave ablation are relatively new percutaneous techniques inclinical use for HCC, that can produce tumour necrosis. Complete response rates are high inlarge series if tumour is less that 3 cm in diameter.

This chapter will consider the main surgical techniques for the treatment of HCC in the lightof the major guidelines currently available and of personal experience.

Also, we will review HCC prognostic factors, and the particular situation of “large” HCC andthe strategy for liver tumours located at the hepato-caval confluence.

2. Surgical approach to HCC

Until two decades ago, prognosis of HCC was considered inevitably poor. Survival values of54%, 40% and 28% at 1, 3 and 5 years in a group of patients with unresectable HCC werereported [5]. Since then, the therapeutic approach and the prognosis have been significantlymodified [6], overall survival rates at 5 yearsreached values of 35-70% for liver resection [7,8] and 40-75% for liver transplantation, depending on the stratification system of patients [9,10]. This mainly related to better allocation of patients to current available treatments (OLT,LR, local therapies), enhancement of post-operative care, and treating patients at centers witha high-volume of hepatic surgeries. With regard to LR there has been an improved balancebetween extent of resection and parenchymal volume spared, a systematic use of intraopera‐tive ultrasound examination (IOUS), and meticulous care to minimize blood loss by mean ofintermittent clamping of the portal triad [11], selective clamping, and use of innovativehemostatic tools for dissection as ultrasound dissectors, harmonic scalpel, and argon-beamers.

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Side by side, some new techniques, such as portal vein embolization to induce hypertrophyof the remnant liver, and intraoperative radiofrequency (RFA) or microwave (MWA) ablationhave allowed it to expand and optimize the surgical offer. HCC occurs in over 80% of cases ofcirrhosis. Furthermore, both tumor and cirrhosis contribute to the risk of mortality, andcirrhosis represents a limit for hepatic resection due to the risk of liver failure.

For HCC arising in the setting of healthy liver, it is undisputed that resection represents thefirst line of treatment; parenchymal resections extended up to 60% of the organ fall within anacceptable risk of post-operative liver failure and mortality.

Conversely, for HCC accompanied by cirrhosis, surgical outcome and prognosis are depend‐ent on the degree of cirrhosis, independent of the tumor stage. In general, considering only thesize of the tumor, three categories of HCC could be defined: (<3 cm), -(3-5 cm), a (5-10 cm) and(> 10 cm). The outcome after resection is good in the setting of smaller tumorsand the resultsafter transplantation are optimal for single tumor<5cm or up to 3 tumors, <3cm each (Milancriteria). Furthermore tumor ablation by percutaneous alcohol treatment or RF ablation isoptimal for tumors in the first category, and in select cases in the second, not applicable fortumors >5 cm. These results depend on the fact that, with an increase in the tumor size thereincreases the likelihood of vascular infiltration, poor tumor grading 3-4, satellites nodules, and/or multinodularity which represent (in particular the first two) a strong negative prognosticfactors. If it is true that the best results in terms of survival are obtained for single lesion, thereis now agreement that multiple nodules, up to 3, and no larger than 3cm can be addressed totransplantation with results similar to those of single tumor < 3 cm. Percutaneous ablativetherapies or multiple resections, or resections supplemented by intraoperative ablation alsooffer discrete survival results in selected cases. The presence of a peritumoral capsule (in theso-called expansive capsulated HCC) represents another favorable prognostic element, whilevascular infiltration, both microscopic and macroscopic, even more drastically reducessurvival expectancy, because it determines an additional risk of early recurrence. Improvedknowledge of the weight of these prognostic factors has led to the development of pathologicalclassification systems very useful for evaluating the prognosis in non-surgical cases. AJCC /UICC pathological classification [12] devotes particular concern to the presence of macroscopicvascular infiltration or infiltration of large venous branches seen on imaging scans, but not tothe size of the lesion, which is useful for prognostic purposes. The classification of the AmericanLiver Tumor Study Group [13] also used by the United Network of Organ Sharing (UnitedNetwork for Organ Sharing - UNOS 2012) [14] takes into account the size and nodularity ofHCC tumors and is used to evaluate patients before resection or transplantation.

Finally, another HCC tumor parameter, which is critical to treatment decisionsis of the tumorlocation within the liver and its relationship with vascular structures. This technical aspectisespecially relevant to small tumors that are centrally located, or close to the main portalbranches or to the hepato caval confluence, which should be considered for percutaneoustherapy or transplantation, given the difficulty of extensive resection in this setting. In addition,other aspects related to the underlying liver disease must be addressed, such as the presenceof portal hypertension (with pressures > 10mmHg), or platelets <100,000 that are associatedwith poor survival outcome following surgery, and increased bilirubin levels.

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3. Liver resection and assessment of liver function

Problems to be faced in order to formulate a correct indication to resection are linked to 1)general conditions of the patient, in particular the presence of co-morbidities, 2) stage of thetumor, and 3) presence of advanced cirrhosis and hepatic function status which represent alimiting condition to hepatic resection and a real risk of postoperative liver failure, this beingthe major cause of mortality.

Liver function in cirrhotic liver is evaluated using different models, none of which is moreuseful than others in predicting of residual liver function after resection. Child-Turcotte-Pugh(CTP) [15] is the functional classification still widely used in most Western Centers: patientswho fall within class A can be submitted to resection, even extended, with a low risk of liverfailure, patients in class B are better candidates for non-surgical procedures (such as RFA, ortransarterial chemoembolization), while those belonging to class C can only aspire to atransplant (Table 1) if within Milan criteria and good surgical candidates. However, theaccuracy of CTP in predicting survival and treatment outcome has been questioned. Further‐more, this classification based only on few functional aspect of the liver is of limited utility ina decisional algorithm that must take into account also pathological aspects of the tumor.

For this reason, attempts have been made to integrate functional aspects of cirrhotic liver andtumor features. An example of these attempts is the Okuda classification (Table 2) [16] whichcombines tumor burden expressed as a percentage value of liver measure (< 50% or > 50%),with other functional and clinical variables: bilirubin and albumin levels, and the presence ofascites. Okuda’s classification is certainly useful for predicting the risk of post-operativecomplications but not the results of long-term survival. In untreated patients with HCC oncirrhosis, this classification has proved to be highly predictive of survival.

Point Bilirubin

( mg/dL)

Prothrombin time Albumin

(g/dL)

Ascites Encefphalopathy

(grade)

1 < 2 "/> 70% "/> 3.5 None None

2 2-3 40-70% 2.8-3.5 Slight 1-2

3 "/>3 < 40 % < 2.8 Moderate 3-4

Stage Score

A 5-6

B 7-9

C ≥ 10

Table 1. Child-Pugh-Turcotte Score

In many Centers, especially Asians, CPT score is supplemented with the indiocyanin greenclearance test (ICG) [17, 18]. Indocyanine Green dye is exclusively cleared from the blood by

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the liver. A value of ICG at 15 minutes ≤ 14% is considered as predictive of a good functionalreserve that allows resection of more than two segments according to Couinaud classification,both in patients in class A as well as for those in CPT class B [17, 19, 20]. Compared to onlyCPT score, ICG15r offers a prediction of the extent of liver resection [11] (Figure 1).

Figure 1. Possible extent of liver resection based on ICGr15 test.

It should be noted that these methods of evaluating liver function do not directly consider thepresence and degree of portal hypertension, which instead is withheld as an high risk factorof post-operative morbidity in most Western Centers. Guidelines of the ’European Associationof the Study of the Liver (EASL 2005) in fact, strongly recommend to preclude resection to

Criterion Cut-off

+ -

Tumor size (*) "/> 50% < 50%

Ascites Clinically detectable Absence

Albumin < 3g/dL "/> 3 g/dL

Bilirubin "/> 3 mg/dL < 3mg/dL

Stage I No positives

Stage II One or two positives

Stage III Three or four positives

Table 2. Okuda staging system. (*) Largest cross-sectional area of tumor to largest cross-sectional area of liver

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patients with portal hypertension (PHT) with hepatic venous portal gradient (HVPG) >10mmHg [5, 21, 22]. According to EASL guidelines, direct measurement of veno-portalgradient is more appropriate than an indirect assessment for the presence of esophagealvarices, splenomegaly, and thrombocytopenia [23]. Recently hepatic elastography, which is ameasure of the parenchymal "stiffness" would seem to linearly correlate with the values ofHVPG, and may be considered as a simple alternative to the direct measurement [24, 25].

Notably, in late 1990s, another classification was proposed, named Barcelona Clinic LiverCancer (BCLC) staging; which takes into account both variables linked to the tumor, andpatient’s conditions (CTP), to be also used as a treatment alloction system (Table 3) [5].

BCLC stratifies patients depending on the size and features of the tumor in four categories orstages: early stage (quite broad: single tumor up to 5 cm in diameter or up to three HCC witha diameter of <3 cm), intermediate stage, advanced and terminal stages. For each category,after considering the performance status, values of bilirubin and presence or absence of portalhypertension, each patient is assigned to a specific treatment modality (resection, transplan‐tation, percutaneous treatment (PEI, RF, MW) which should offer the expectation of survivaland treatment outcome.

Stadio Tumor features Clinical features

Stage A (EC early)

A1 PST 0 Single tumor Portal hypertension absent, normal

bilirubin levels

A2 PST 0 Single tumor Portal hypertension present, normal

bilirubin levels

A3 PST 0 Single tumor Portal hypertension present,

abnormal bilirubin levels

A4 PST 0 3 nodules less than 3 cm Child Pugh A-B

B (EC intermediate) PST 0 Multinodular Child Pugh A-B

C (EC advanced ) PST 1-2 Vascular infiltration and extrahepatic

extension

Child Pugh A-B

D (EC end stage) PST 3-4 Any Child Pugh C

Table 3. BCLC staging system (Barcelona Clinic Liver Cancer). PST: performance Status Test.

Notably, the American Association for the Study of the Liver guidelines (AASLD) [26], adoptedBCLC HCC staging. The Asia-Pacific Association for the Study of the Liver (APASL) [27]maintained a bolder position: it does not evaluate a "functional reserve", and even puts a limitin the presence of portal hypertension, reflecting different development experience in EasternCenters. The gap between the two guidelines is expanded even more if it considers the tumorburden, in fact AASLD guidelines recommend liver resection only in the presence of a singleHCC, while APASL guidelines allows resection if HCC is confined to the liver, if the portal

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trunk is patent and the resection technically feasible, verbatim “Liver resection is a first-linecurative treatment of solitary or multi-focal HCC confined to the liver, anatomically resectable,and with satisfactory liver function”. This recommendation is obviously very different fromthat of the AASLD, verbatim “Patients who have a single lesion can be offered surgicalresection if they are non-cirrhotic or have cirrhosis but still have preserved liver function,normal bilirubin and hepatic vein pressure < 10 mm Hg”.

Thus, HCC staging and treatment allocation reflect a certain methodological variability [28]determined by ethical and social influences, and different practical needs of the different healthcare systems worldwide, which ultimately produce center-specific selection criteria.

4. Indication to liver resection

Resection for HCC is placed on the basis of two preliminary “technical” considerations:

1. Amount of liver function reserve and value of residual liver volume (RLV).

2. Anatomical location and extent of the tumor.

Single HCC below 5 cm, or multifocal HCC (not more than three tumors) without vascularinvasion and with limited dimensions (<3 cm each), offer very good survival results that reach50% at 5 years [29–31], and up to 70% at 5 years in a category of patients with normal bilirubinvalues and absence of portal hypertension [5]. In view of these results, there is a rather frequentdisease relapse, estimated in terms of 50% at 3 years, 70% at 5 years and > 80% at 10 years [29–32]. Since these hopeful survival results (in particular for single HCC < 3 cm) were consistentwith those of percutaneous ablation therapies, and slightly lower than those of transplantation,the choice of the procedure essentially depends on the experiences of the treating center [26].

The best results in terms of survival and low disease recurrence are offered by transplantspecially in cases with established cirrhosis, even if, on a basis of "intention-to-treat" compar‐ison the difference tends to be closer [33]. However, the option of liver transplantation is clearlylimited by the shortage of organs supply. In 2010, based on the Organ Procurement andestimated Transplantation Network (OPTN), average waiting list time ranged from 140 daysfor American Indians up to 651 days for Hispanics [34]. Depending on the wait time periodand the selection criteria used, the dropout rate for patients with HCC awaiting LT rangedbetween 12% and 38% [10, 35–37], and was essentially linked to tumor progression. Therefore,for early stage HCC transplantation should be reserved for those patients with poor liverfunction (eg CPT class C), and/or with evidence of portal hypertension. Since the report fromMazzaferro on the results of liver transplantation in a very well defined category of HCC, withactuarial 4-year overall survival of 85% and disease-free survival of 92%, subsequentlyconfirmed by others, the "Milan criteria" [9] has marked an important turning point towardsa more homogeneous transplant indication. Subsequently, other centers [38] have attemptedto expand these criteria with fairly consistent results. However, the favorable results oftransplantation for HCC within the Milan criteria must be considered very carefully, becauseit may be influenced from a selection bias. In fact, stratifying patients for factors other than

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size (for example for the presence of vascular invasion), survival curves between OLT and LRshowed a similar trend [39]. Many high volume centers for HCC treatment reported thatpatients eligible for OLT (within the Milan criteria), but subjected to liver resection showed 5-year actuarial survival rate of about 60-70%, [6, 8, 40–45], in particular in a subgroup of patientswithout vascular invasion [39, 42–48].

Taking into account these observations, it seems appropriate to offer hepatic resection topatients with preserved liver functions who may be also eligible for transplantation, thanks tothe rapidity of care, the greater simplicity of resection compared to transplant, and the lowerrate of post-operative morbidity and mortality. Furthermore, it must be considered thattransplant exposes patients to the risk of toxicity and potentially fatal infections related toimmunosuppressive therapy, and predispose to the development of "de novo tumors".

In contrast, as previously mentioned, resection is associated with a higher recurrence rate(50-70% at 5 years) given the persistent background defect of the underlying liver disease thatled to HCC development in the first place. Liver recurrence could be managed surgically (witha re-resection) in selected cases, or through the use of percutaneous ablative therapies, or bymean of “salvage transplant”. Recurrences rates are lower if tumors are within the Milancriteria could benefit after orthotopic liver transplant as well as from split liver transplantation(SLT), the latter, using of a portion of liver from a living or dead donor, allows a more rapidaccess to liver transplantation. Two recent studies showed 5-year survival, morbidity andrecurrence rate after salvage transplant to be similar to OLT performed as first choice [41, 49].

Recurrence is influenced in part by HCC pathological criteroa such as satellites nodules,vascular invasion, and poor histologic grading G3-G4. Translational research aimed atidentifying molecular characteristics of HCC predictive of high risk of recurrence will bepromising to avance this area of clinical challenge. Thus far, different chemoterapeutic agentshave been tested in the adjuvant setting to reduce the recurrence rate. However, the smallnumbers of patients and the confounding variables did not lead to conclusive results.

The evidence gained to date for reducing the risk of recurrence has been linked to the surgicaltechnique details. In particular, during the exploratory time, intraoperative ultrasonographyshould be systematically used for the correct evaluation of the position of the lesion, for theexclusion of further lesions not identified at pre-operative imaging, and yet for a correctevaluation of the vascular anatomy (Figure 2). It is estimated that 22 to 35% of the plannedresections could change as a result of the IOUS examination.

HCC tend to permeate portals pedicles causing "anatomical" metastases or tumor thrombi thatin turn are responsible of liver metastases (Figure 3). For this reason, many surgeons prefer toperform anatomical segmental or sub-segmental resections rather than atypical or wedgeresections to ensure the inclusion of any microscopic satellite nodules, and tumor segmentalembolization [50]. The advantage of anatomic resections remains valid, even in cases ofmultifocal lesions, as an alternative to extended resections such as hepatectomy or extendedhepatectomy, given the advantage of preserving the hepatic functional reserve [51]. In the caseof small centrally located HCC, and/or HCC proximal to major vascular pedicles, extensiveresections are required [52], but alternatively bi- or three-segmentectomy whenever feasible,

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offers the same oncologic advantage, and at the same time allows a second surgical approachin case of relapse. Central resection (segments 5, 8, and 4), anterior-central resection (segments4b and 5), posterior-central resection (segments 4° and 8), and lateral-superior bisegmentec‐tomy (segments 7 and 8), and inferior-right bisegmentectomy (segments 6 and 5) represent aneconomic alternatives to standard right hepatectomy.

The segmental nature of the liver has been reported by Bismuth [53] who described eightsegments, each of which is provided by an independent artero-portal and biliary pedicle.Segments are easily identified by anatomical landmarks, or through the intraoperativeultrasonography study of the portal branches distribution. A clear segmental demarcationcould be obtained through by ultrasound-guided direct puncture and flushing of the portalbranch with intravenous dye (methylene blue) tattooing the liver surface corresponding to theperfused district; using small bilumen-catheters equipped with inflatable balloon, and theSeldinger technique it is possible to simultaneously tattooing the liver surface (Figure 4) andoccluding the vascular lumen in order to stop blood flow to the segment, minimizing bloodloss, and theoretically reducing the risk of retrograde embolization from the tumor.

In general HCC ≤ 3cm can be treated with a segmentectomy, or with sub-segmentectomy, HCC3-5 cm with segmentectomy eventually extended to contiguous subsegments, HCC> 5 cm mayrequire more extensive resections in order to provide a free margin from neoplasm of at least1 cm (Figure 5).

Figure 2. Intraoperative ultrasound examination showing a small HCC of 2 cm (star mark) located in the eighth seg‐ment and two minimal HCC (5 and 4 mm) (arrows) in the contiguous seventh segment. The planned resection of theeight segment was changed to a bisegmentectomy of 7+8.

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With regard to the definition of the so-called "high-risk HCC", it is still controversial. The high-risk HCC could be defined as:

1. “large”, those > 5 cm in diameter (Figure 6). Large HCC increases the risk of vascularinfiltration, worsening the prognosis. Even 10 years ago, 5-year survival after resection wasno more than 33%. Today survival rate for large HCC without vascular infiltration arereported to be about 70% at 5 years [54] and 45% for so-called “giant HCC” (> 10cm) [55].

Figure 3. Modality of intrahepatic spreading of HCC. Tumor infiltrating sub-segmentary portal branches and deliver‐ing tumor cells to the perifery (intra-segmental diffusion) (left). Tumor thrombus has invaded a portal pedicle and be‐comes a source of dissemination at distance (intra- extra-segmental diffusion) (right).

Figure 4. Technic of tattooing liver segment. Staining a segment through a bilumen catheter introduced according toSeldinger technique, after direct puncture under US guidance of a segmental portal pedicle (left). Blood flow occlu‐sion inflating the balloon (optional) (center). Division of the parenchyma in segmental ischemic condition (left).

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2. “multifocal tumors”. Multifocality was considered for a long time as a contraindicationto surgical approach, since it is associated with a poor prognosis. The only feasibletreatment within the limits of small dimensions (3 nodules < 3cm each) is liver transplan‐tation. However, many patients do not fall within the selection criteria and about 20% ofthose selected experience progression and dropout from the waiting list. Thus, surgicalresection for patients with preserved liver functions may be the only curative option formultifocal HCC. Global survivals from 29.9% to 58% are reported at present, dependingon the selection criteria [56, 57].

3. “macroscopic portal/hepatic vein involvement”. This condition indicates the worstprognosis with a life expectancy of a few months in the absence of treatment.

In general, resectability for high-risk HCC is considered in absence of extrahepatic disease(lymph node metastasis or extrahepatic hematogenous spread and contiguous organsinvolvement), and in presence of preserved liver function. Due to the size, number, locationand vascular involvement of the tumor, major resections or multiple resections are required,and are often associated with vascular reconstruction procedures. Limits to indication are thepercentage value of the estimated remnant liver, and feasibility of vascular reconstruction.This configure a complex liver surgery that exposes at significatively higher morbidity/mortality risk and different survival rates depending on specific Centers selection andinfluenced by three main prognostic factors: grading, vascular infiltration, and size of thetumor. However, if resection is technically feasible, long-term survival for these patients isbetter than second-line therapy as trans-arterial chemo-embolization (TACE) [58, 59].

For multifocal and bilobar HCC although there are no randomized trials,there is anevidenceof cohort studies that rported successful resection in select cases [60, 61]. Resection can be

Figure 5. Tattooing of sub-segment of the fifth segment for a small HCC deeply located.

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combined with intraoperative ablation (RFA) expanding the rate of curability. Overall 5 yearssurvival between 39% and 58% for large, multifocal and vascular infiltrating HCC [57, 58, 62–65] compared with the results of TACE overall survival of 24-63% at 2 years, and lowest rateof survival at 5 years [66–68].

Recently, Delis [69] compared a group of 59 patients within the UCSF (abbreviation needs tobe defined..) liver transplant criteria (single tumor ≤6.5 cm, or three or fewer tumors of whichthe largest ≤4.5 cm and the sum of the tumor diameter ≤8 cm) [38] and another group of 27pateints who exceeded these criteria: all patients underwent hepatectomy or extendedhepatectomy with no mortality, but with higher rates of complications in the group thatexceeded the UCSF criteria. 1, 3 and 5 years disease-free survival were 66%, 37% and 34%,respectively, in the first group and 56%, 29% and 26%, respectively, in the second group (p<0.01), and the rate of recurrence was significantly higher in the second group, 74% vs 69% (p<0.002). Vascular invasion was a strong predictive factor of intrahepatic and distant recur‐rences. Therefore, major vascular invasion is considered a contraindication to surgery andtransplant in many surgical centers. Ikai [62] reports results of 66% and 43% 5-year survivalin HCC with and without vascular infiltration, and found better survival values for the caseswith tumor invasion of the portal branches of 2nd and 3rd order compared with invasion ofthe portal trunk or main branches, or contralateral infiltration. The recurrence rate was high(percentage??), but a considerable proportion of cases may be candidates for re-resection orablative treatments. In the presence of tumor invasion of the portal trunk, 5-year survival of26.4% is reported (thrombosis with portal infiltration) and 28.5% (p =.33) (without portalinfiltration) [70]. According to some authors pre-treatment with TACE before resection canincrease the global values of 5-year survival up to 42% that is a value significantly higher than7% observed in non resected patients [71]. Resection and reconstruction of the portal trunk or

Figure 6. A case of very large, or so-called “giant HCC” which measured > 30 cm in diameter and weighted 5 Kg, in‐volving the entire right hepatic lobe. The tumor did not involve the portal trunk and the left lobe was hypertrophic.Note the ischemic demarcation line (arrows) after selective right pedicle clamping.

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of the main portal branches represent a very small percentage of the total resections, but theyimpose considerable technical difficulty because they require mobilization of the portal veinto the pancreas, an accurate posterior skeletonization, and dissection of the contralateral portalpedicle before the venotomy.

In the presence of hepatic veins involvement resection also extended to venous segments isaccompanied by global survival at 1 and 3 years of 88% and 50% respectively, with mortalityrates of 12% [72]. These are very selective indication procedure, which must be addressed athighly skilled centers in the hepato-biliary-pancreatic surgery.

In conclusion, for high-risk HCC there are no guidelines supported by strong scientific evi‐dence at the moment, but nevertheless, resection is offered more frequently in both Eastern andWestern Centers as well as in Academic Centers with a high volume of liver surgery [73–75].

5. Technical details

Major resection, defined as the resection of more than two segments (on liver with chronicdisease), does not involve particular risks of liver failure in patients with preserved functionalreserve (CTP class A), which can tolerate even more extensive resections, such as right or lefthepatectomy. However, except for cases of large HCC where the resected liver accounts for asmall proportion of functioning liver parenchyma, in other cases it is appropriate that a greaterhepatectomy is replaced by more limited resections, allowing to reduce the risk of postoper‐ative liver failure, and maintaining the chance of a new intervention in case of recurrence.

As aforementioned, the choice of a segmental resection is standard because it reduces theincidence of early complications, such as seromas, abscesses and in particular biliary leak. Thisaspect should not be underestimated since postoperative infection could lead to increased riskof liver failure.

An adequate knowledge of the vascular anatomy of the liver, the improvement of surgicaltechnique and post-operative care have allowed to extend resections for large tumors, selectcases of majorvascular involvement, saving the functioning segments, such as the salvage ofsegment 6 to preserve the portal postero-inferior pedicle, or reconstructing hepatic vessels inorder to avoid vascular congestion of residual segments and/or sectors (Figure 7). Vascularreconstruction can be of direct-type as hepato-caval, or with prosthetic interposition (generallyGore-Tex), or venous segment interposition (portal or gonadal). This procedure can beperformed with direct vascular control, or with ex-vivo technique using veno-venous bypass.Vascular reconstructions have the main purpose of avoiding the congestion of segments thathave no other way of direct outflow [76]. For these techniques a complete study of vasculardistribution preoperatively with CT-angiography and intraoperatively by mean of ultraso‐nography is mandatory.

Intraoperative bleeding represents a further technical problem., In fact, blood loss affects boththe patient outcome in the short term, as well as the long-term survival and relapse. In the case

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of cirrhotic patients, bleeding is a cofactor of liver failure. Currently in high volume centersfor liver surgery, 50-70% of resected patients do not require blood transfusions.

To limit blood loss, Pringle maneuver or clamping the portal triad are the technique mostcommonly used. Intermittent clamping of the hepatic hilum is preferred in cirrhotic patientscompared to continuous clamping aimed to limit ischemia/reperfusion damage. Typically,clamping that determines a state of warm ischemia, is prolonged in cirrhotic up to 15 minutes.In the case of prolonged resection times clamping can be repeated with periods of unclamping(reperfusion) of 5 minutes (intermittent clamping). To limit the risk of ischemia/reperfusiondamage many surgeons employ the technique of pre-conditioning, which consists of 10minutes clamping followed by 10 minutes reperfusion, which precedes the definitive clamp‐ing. Pre-conditioning is believed to adapt liver parenchyma to warm ischemia thus reducingthe damage of ischemia/reperfusion. In fact, there is much evidence of this advantageous useof the pre-conditioning in animal studies. However, evidence from few clinical studiesdoesnot conclude potential definite benefit in humans [77–79].

An elegant and effective alternative to the Pringle maneuver is vascular direct control by meansof ligation and division of the portal and arterial branches of the hepatic lobe to be resected ifa hepatectomy is planned, or its selective clamping in the course of segmental resections; thusmaintaining blood flow to the contralateral lobe. The selective exclusion of blood flow isconfirmed by a change in color (ischemic demarcation) on the surface of the liver lobe excluded.Typically, if resections are performed with vascular control outset, the hepatic vein drainageis identified and secured too, thus causing a total parenchymal ischemia. Under certain

Figure 7. Direct reconstruction of the middle hepatic vein (white arrows) after resection of HCC situated between seg‐ment 8 and 4a. The yellow arrow indicates the upper segmental branch for segment 8.

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favorable circumstances of anatomical dissection (easy hilum), inflow vascular control can alsobe obtained on second order branches (sectorial pedicles) determining a super-selectiveischemic control.

Clamping of the hepatic vessels is generally employed during major resections, while it is notnecessary if a small segmental resections, or wedge and laparoscopic resection are carried out[80–82].

The interruption of the blood flow from the hepatic pedicle effectively reduces bleeding duringtransection; however, bleeding could still results from the hepatic veins branches. To limit thisfurther source of bleeding, it is useful to conduct resection under low value of central venouspressure (PVC) at less than 5 mmHg, and to place the patient in 20-25° Trendelemburgdecubitus. The value of CVP in fact is reflected both at the level of the hepatic veins as well asat the sinusoidal compartment level, and blood volume lost during resection well correlateswith the value of CVP [83–86].

Intraoperative control of bleeding is further optimized by the use of different instruments ofparenchymal dissection, all aimed at containing bleeding from venular or sinusoidal origin.Classical hepatic dissection is carried out through parenchymal crushing by means of the Kellyor Klemmer clamps (crushing clamp technique): clamp pressure fractures the parenchymaleaving uncovered blood vessels that, depending on the size, are secured by mean of coagu‐lation device or sutures or clips. Alternatively one can employ tools that divide the parenchymain a gentler manner, through the ultrasonic dissector (ultrasonic dissection - CUSA-), bipolarcurrent instruments (LigaSure), or radio frequency device (Harmonic Scalpel), to list a fewexamples. Although simple to use, the usefulness of these instruments is not clearin terms ofblood saving or shorter time of resection[87].

Another technical consideration related to expanding the possibility ofresection even in thosecases in which the total liver remnant volume is < 30% in healthy liver or < 35-40% in cirrhoticliver is expected, which are the limits generally accepted to contain the risk of postoperativeliver failure [88, 89]. It is in fact possible to increase the volume of the hepatic remnant throughthe mechanism of liver lobe induced hypertrophy occluding the contralateral portal branch,the so-called portal vein embolization (PVE). This procedure is generally carried out underlocal anesthesia, through the puncture of a portal branch under ultrasound guidance or byfluoroscopy, which is then occluded by different embolizatin materials. This techniquedetermines a volumetric increase of the residual lobe of about 8 to 12% over the time of about20-30 days. After PVE, the percentage of patients undergoing surgery ranges from 62 to 100%according to recent studies [90, 91].

6. Indication to orthotopic liver transplantation

Since 1968 the "European Liver Transplant Registry” (ELTR) records all data of liver trans‐plants in 145 centers across Europe. These data give an overview on what is the trend oftransplants in Europe during each period.

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Both the number of centers and the number of liver transplants gradually increased, but afteran exponential growth until the 80s, they reached a plateau that was maintained as shown byrecent data (ELRT) with about 5800 liver transplants performed per year across Europe.Cirrhosis was the most common indication for liver transplantation (52%) rate, followed byprimary tumors of the liver (14%, HCC 12.1%).

Indication for liver transplantation have significantly changed over time. Subsequently, therate of liver transplantation for increased to 20% in late 1990s. Between 2000-2010, two groupsof indications have increased: primary tumors of the liver (16%), especially HCC, and cirrhosis(53%), especially alcohol related (20%).

Transplantation for HCC has thus become a therapeutic approach more commonly used inEurope where it accounted for 25% of all indications for liver transplantation. Improvementof survival of cirrhotic patients given by the pharmacological control of HBV and HCV, hasled to an increased rate of survival and lower rate of recurrent HCC. In fact, HCC has graduallybecome the most common complication in cirrhotic patients. In the last three years the numberof patients with HCC in transplant list has grown dramatically: more than 30% in France, 26%in Europe, 34% in the United States [92, 93].

7. The role of liver transplant from living donor

Living donor liver transplantation (LDLT) is a practice used mainly in Asia, where orthotopicorgans are not readily available. Its use was later extended to other countries, mostly in Europeand North America to compensate for the shortage of organs and the long time on the waitinglist which leads to patients’ death, or dropout for medical reasons or progression of cancerbeyond acceptable transplant criteria.

The main requirement of the transplant from a living donor is the "donor safety", namelythe protection of the donor. Although the risks of this intervention in specialized centers arevery low, the incidence of death of the donor ranges from 0.15 to 0.30%, but can reach up to0.50%. The concept of "double equipoise" was proposed to describe the balance that must bemaintained between the benefits related to the survival of the recipient and the risk ofmorbidity/mortality of the healthy donor. For example, in Europe and North Americatransplantation for acute liver failure from a living donor is not accepted, as the mortality ofthe recipient in such cases is higher. Some studies have suggested a higher risk of tumorrecurrence related to liver regeneration after transplantation using a hemiliver from livingdonor compared to cadaveric whole liver. Other studies have shown no significant differen‐ces related to the type of graft used, and the only risk factor appeared to be related to thetiming of transplantation from a living donor (fast-tracked patients), a short interval betweenthe diagnosis of HCC and transplantation whaich can lead to a greater risk of tumorrecurrence in the short term related to the fact that the biological behavior of HCC has notyet fully manifested. For these reasons, it is generally required to have a wiat time ofat leastthree months between the diagnosis of HCC and transplant before offering a graft from aliving donor. The transplant from a living donor is acceptable if the 5-year survival is

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comparable to that of patients transplanted from cadaveric donor. The use of cadaveric donorsin the event of failure of the graft is generally accepted. The need for re-transplantation isstill very low however, and the survival after re-OLT is high. In patients transplanted forHCC from a living donor within regionally accepted criteria, re-transplantation for graftfailure using a cadaveric liver is also possible and accepted by the scientific community. Ifthe transplant from a living donor had been done over the criteria, re-transplant from acadaver is not recommended [94–98].

8. Inclusion criteria

Currently, in many countries, the eligibility criteria for transplantation for HCC follow "Milancriteria" [9]:

• the presence of a single tumor of less than or equal to 5 cm in size;

• up to three tumors of size less than or equal to 3 cm;

• absence of extrahepatic or lymph node metastases;

• absence of tumor thrombosis of the portal veins, or hepatic veins per liver imaging.

The tumor should be considered unresectablebased on the location, major vessel involvement,or if the tumor is multifocal or the patient has advanced cirrhosis (Child class B or C) [9, 99].

The expansion of the Milan criteria with the criteria of San Francisco (1 nodule < 6.5 cm indiameter or multiple nodules of 4.5 cm in diameter with the sum of the diameters < 8cm)had mixed results in terms of survival (survival at 5 years of 50%); for patients with HCCoutside the limits of the criteria of Milan, the survival tends to decrease mainly in therecurrence of disease. Survival that is reduced to less than 50% at five years after transplan‐tation is considered not acceptable. Given the scarcity of available organs, many countriescircumscribe selection of patients exclusively to the Milan criteria. In practice, the problemof the shortage of organs is the principal factor influencing the indications for transplanta‐tion. Therefore, it became mandatory to tranplant only patients who can reach an adequatesurvival.

The "United Network of Organ Sharing or UNOS" has rejected the use of CTP classification toprioritize HCC patients on the waiting list, who may have an increased risk of mortality whileon the waiting list. The MELD system became the standard method for assessing the clinicalseverity of a patient potentially candidate for liver transplantation. It is based on a numericalscore that takes into account the levels of serum creatinine, total bilirubin and INR. The scoreis calculated according to the formula:

9.57*log (creatinin mg/dl) + 11.2*log (INR) +3.78*log (Bilirubin mg/dl) + 6.43

This formula calculates the risk of 3-months mortality. Patients with high scores have priorityon the waiting list for transplantation [100].

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The limit above which a patient can be enrolled into a waiting list is of MELD 15; wheneverthe MELD is less than 15 the risk of the transplantation is certainly greater than the risk ofmortality by three months in the absence of transplantation. Since patients with HCC oftenhave a MELD < 15 and therefore a lower priority of transplantation, UNOS considered to assignall patients with HCC (T1-T2) a MELD of 22, regardless of the actual state of liver disease. This,however, several others factors are still considered.

In addition to the number and size of lesions (Milan criteria) and serum creatinine, bilirubinand INR (MELD score), great importance is also given to the values of the α-FP. Althoughthere is not a cut-off default, in patients with cirrhosis and HCC, if α-FP levels is increasing bymore than 15 microg / L per month, liver transplantation is associated with a 5-year survivalof less than 54%. Consequently, α-FP is considered a marker of related HCC aggressivenessand therefore should be considered to select potential candidates [101].

9. Prognosis

The main causes of death after liver transplantation are:

• Perioperative generalized morbidity causes such as multi-organ failure, cerebrovascular,cardiovascular, pulmonary and renal complications (29%).

• Recurrence of the primary disease (20%), especially tumors (11%).

• Sepsis (18%), especially bacterial (9%).

• Technical complications (5%), especially bleeding and vascular disorders (3%).

• Rejection (4%), especially chronic (3%).

Intraoperative death and liver failure represent 3% of all deaths.

Over the past 10 years there is a decrease in mortality in the range of 16%.

Survival after transplantation account for 82% at 1 year, 71% at 5 years, 61% at 10 years, 51%at 15 years and 43% at 20 years.

Survival has improved over the time reaching 85% at one year in 2004, compared to 76% in1990-1994 to only 33% in 1985 (please list reference(s)..). This improvement over the time ismost evident in liver transplantation for liver tumor.

From 1988 to 2009, 5-year survival was statistically higher for patients with cirrhosis (72%)than in patients with primary liver cancer (52%). During the last 10 years, post transplantsurvival for cirrhosis and liver cancer tended to approach (73 vs. 64%).

Moreover, a recent multicenter study from Europe showed that cumulative 1 and 5 yearsurvival for patients transplanted for HCC on cirrhosis is 86% and 70% respectively in patientswithin the Milan criteria. Patients beyond the Milan criteriahad an average overall 5-yearsurvival of 61.5% (correct?) [92, 102].

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Etiology of liver disease

and (n. TX)

Years (1999-2009)

1 year actuarial survival (%) 5 years actuarial survival (%)

Graft (%) Pazient (%) Graft (%) Pazient (%)

Acute hepatic failure

(3449)70 76 62 69

Colostatic disease (4675) 83 89 74 81

Congenital biliary

pathology (2167)84 90 79 87

Cirrhosis (25424) 81 85 69 73

Primary liver tumors

(7640)81 83 61 64

Metastatic tumors (361) 77 83 50 55

Metabolic diseases

(2866)82 87 72 79

Budd Chiari (400) 76 81 66 73

Table 4. Patients and graft survival over the last 10 years (adat from European studies of liver transplant for HCC(correct?). Modified from [92]

10. Follow-up and treatment of recurrence

The main concern for patients subjected to liver transplant for HCC is recurrence that occursin 8 to 20% (reference). Recurrence usually occurs within the first two years and is associatedwith a median survival of less than one year from the time of diagnosis (range 7-18 months).The adoption of α-FP assay and imaging (ultrasound, CT and MRI) every six months in thecourse of the follow-up has resulted in early detection of recurrence, allowing for a possibletreatment to more than 1/3 of the cases.

Recent studies have tried to identify the role of post-transplant adjuvant therapy, but results,while highlighting a benefit in terms of overall survival and disease-free interval, are notconclusive because of their variability in terms of chemotherapeutic regimen, dosage, inclusioncriteria and end points.

Sorafenib is a tyrosine kinase multi-targeted inhibitor, approved for treatment of patients withadvanced HCC. However, its use post-transplant is not permitted outside of clinical trials.Loco-regional therapies for HCC recurrence (RF, TACE) and resection have been used inpatients with limited burden of disease and appear to be useful in selected cases. In conclusion,the HCC recurrence after transplantation provides surgery for resectable lesions or throughloco-regional therapies or systemic therapies (including Sorafenib) for unresectable lesions.Liver re-transplantation for HCC recurrence is not established [103–106].

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11. Summary

Surgical treatment of HCC has evolved over the last 20 years due to improvements in surgicaltechnique, anesthesiologist care and in particular to more appropriate criteria for carrying outresection or liver transplantation. Using systematic screening of at-risk groups has increasedthe detection of HCC at an early stage, potentially curable.

Survival rates following HCC surgical treatments, which were disappointing in the past, arevery high today exceeding 50% at 5 years, both with resection as well as with transplantationin the category of single and small HCC. The choice between transplant and resection iseventually related to liver function that may be compromised by coexisting cirrhosis, and theavailability of grafts that is currently lacking.

The biggest flaw of hepatic resection remains its high rate of relapse of the disease. In part, dueto true recurrence, and partly due to the emergence of new HCC. In this situation it is possibleto consider a transplant rescue, a second resection or local therapy options if the disease islimited to the liver, or systemic therapies if metastatic.

A most relevant concern remains that of high risk HCC for which transplantation is precluded.In this category of HCC resection with very strict indications can still meet a decent expectationof survival.

Author details

Alessandro Uzzau1*, Maria Laura Pertoldeo1, Vittorio Cherchi1, Serena Bertozzi1,Claudio Avellini2 and Giorgio Soardo1

*Address all correspondence to: alessandro.uzzau@uniud.it, alessandrouzzau@gmail.com

1 Department of Clinical and Experimental Sciences, University of Udine, Italy

2 Department of Biological and Medical Sciences, University of Udine, Italy

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